The primary goal of this project is to use differences in the human response to a single vaccine antigen to determine factors that are critical to the ability of an individual to make a protective response to the vaccine. The vaccine antigen used in these studies is the major surface antigen of Hepatitis B virus, HBsAg. Using a broad range of tools, including genome-wide transcriptional profiling, multiparameter flow cytometry and detailed functional phenotyping of antigen-specific T cell subset, we will determine which components of the innate and adaptive response to vaccine correlate best with the seroprotective response to vaccination. The major part of this project will be a systems biology study of the same antigen, HBsAg, with two different adjuvants. Alum and the Toll-like receptor-9 agonist, CpG-ODN. Clinical trials have shown CpG-ODN to be a much more effective vaccine, especially in subjects that respond poorly to vaccination due age or disease. We propose to compare transcriptional and cellular responses to these two adjuvants in older healthy adults and later in patients with end-stage renal disease of HIV infection. This study presents a unique opportunity to study in humans the mechanisms of action of the most widely used adjuvant, alum and one of the most promising modern adjuvant candidates, CpG-ODN, in a study in which the adjuvants are the only significant variable. These studies will constitute an important advance in our understanding of the actions of adjuvants and will hopefully identify the primary reasons for unresponsiveness to vaccination in older adults and in specific disease states.